The goal of the proposed project is to use time-reversal acoustics (TRA) focusing of ultrasound to improve the effectiveness of convection-enhanced delivery (CED) of drugs to the brain. CED is a promising method of drug delivery to the brain for the treatment of several disorders, including glioblastoma multiforme, a high-grade glioma that presents an especially poor prognosis for patients. CED bypasses the blood-brain barrier by infusing compounds through a needle directly into brain parenchyma or brain tumor. CED has been tested extensively in animals and humans to deliver a variety of agents including small molecules, proteins, chemotherapeutics, and viral vectors. Preclinical and clinical studies suggest that the outcome of the therapy depends strongly on controlling the spatial distribution of the infused material once it has been infused into the brain. Therefore, any technique that increases the penetration distance and provides control over the spatial distribution of the infused material could significantly improve the efficacy of CED in clinical practice. We have previously shown that ultrasound can enhance the transport of infused molecules in CED. Now, we intend to use TRA focusing to control the spatial distribution of the infused material. TRA is an efficient method of focusing ultrasound in heterogeneous media, especially inside reverberating cavities, such as the skull. We have developed a smart needle that is a CED infusion catheter containing a miniature transducer at its tip, which acts as a beacon for focusing ultrasound. Our goal in this application is to demonstrate that the TRA system can be used to focus ultrasound in three-dimensional volumes that match a lesion or other target tissue in the brain. Then, we will demonstrate that fluid infused by CED preferentially fills the regions of focused ultrasound. A series of experiments using human skull models will be carried out to determine the optimal ultrasound parameters for accurate focusing in volumes with complex shapes. Then, the results of the studies in models will be confirmed by experiments in the rodent brain in vivo. This will be first demonstration of a method to control the spatial distribution of infused fluid in CED, which has the potential to significantly enhance patient outcomes of this critical therapy. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a therapeutic ultrasound device to control the distribution of chemotherapeutic agents in the brain infused using convection enhanced delivery for the treatment of brain cancers. The technology, approach and knowledge gained from using therapeutic ultrasound fields to control drug distribution may have far reaching medical and research applications.